Replication and validation of genetic polymorphisms associated with survival after allogeneic blood or marrow transplant

Abstract

<p id="d5634714e388"> <div class="list"> <a class="named-anchor" id="d5634714e390"> <!-- named anchor --> </a> <ul class="so-custom-list"> <li id="d5634714e391"> <div class="so-custom-list-content so-ol"> <p class="first" id="d5634714e392">Candidate SNP associations with survival outcomes after URD transplant are most likely false-positive findings. </p> </div> </li> <li id="d5634714e394"> <div class="so-custom-list-content so-ol"> <p class="first" id="d5634714e395">Over 85% of candidate SNPs are not linked to a biochemical function; of those that are, about half are not linked to the candidate gene. </p> </div> </li> </ul> </div> </p><p class="first" id="d5634714e400">Multiple candidate gene-association studies of non-HLA single-nucleotide polymorphisms (SNPs) and outcomes after blood or marrow transplant (BMT) have been conducted. We identified 70 publications reporting 45 SNPs in 36 genes significantly associated with disease-related mortality, progression-free survival, transplant-related mortality, and/or overall survival after BMT. Replication and validation of these SNP associations were performed using DISCOVeRY-BMT (Determining the Influence of Susceptibility COnveying Variants Related to one-Year mortality after BMT), a well-powered genome-wide association study consisting of 2 cohorts, totaling 2888 BMT recipients with acute myeloid leukemia, acute lymphoblastic leukemia, or myelodysplastic syndrome, and their HLA-matched unrelated donors, reported to the Center for International Blood and Marrow Transplant Research. Gene-based tests were used to assess the aggregate effect of SNPs on outcome. None of the previously reported significant SNPs replicated at <i>P</i> &lt; .05 in DISCOVeRY-BMT. Validation analyses showed association with one previously reported donor SNP at <i>P</i> &lt; .05 and survival; more associations would be anticipated by chance alone. No gene-based tests were significant at <i>P</i> &lt; .05. Functional annotation with publicly available data shows these candidate SNPs most likely do not have biochemical function; only 13% of candidate SNPs correlate with gene expression or are predicted to impact transcription factor binding. Of these, half do not impact the candidate gene of interest; the other half correlate with expression of multiple genes. These findings emphasize the peril of pursing candidate approaches and the importance of adequately powered tests of unbiased genome-wide associations with BMT clinical outcomes given the ultimate goal of improving patient outcomes. </p>